Tag: Glioblastoma

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Isocitrate Dehydrogenase Wild-type Glioblastoma Resection Under Fluorescein Sodium and White Light Guidance Based on Response Assessment in Neuro-Oncology Resect Criteria

Operative Neurosurgery 30:861–869, 2026

This study evaluates sodium fluorescein–guided resection versus white‑light surgery in isocitrate dehydrogenase wild‑type glioblastoma, using RANO resection classes and quantitative MRI volumes to compare residual contrast‑enhanced tumor burden. The retrospective analysis of 162 patients shows significantly lower postoperative CE residual volume and higher complete CE resection rates with fluorescein guidance.

The paper also correlates molecular markers with resection outcomes, finding MGMT promoter methylation associated with higher complete CE resection rates and suggesting fluorescein guidance may particularly improve CE resection across molecular subgroups, while survival differences require longer follow‑up and larger cohorts.

Objective Increase extent of resection of the contrast-enhanced (CE) portion of IDH–wild-type glioblastoma, using the RANO absolute residual-volume resection classes to quantify what sodium fluorescein guidance achieves vs white light (WL) surgery.

Design/measurement Retrospective comparative study of 162 patients (fluorescein 82 vs WL 80), with pre/post-op MRI volumetrics outlined in Brainlab and categorized by RANO EOR classes.

Key EOR result Residual CE tumor volume was lower with fluorescein guidance than WL (median 0.0 cm³ vs 0.5 cm³, P = .023).

Complete CE resection rate Proportion with 0 cm³ residual CE (RANO I + IIA) was higher with fluorescein (62.2%) than WL (42.5%), P = .012.

RANO distribution shift RANO class distribution differed between groups (P = .015), with more IIA and fewer IIB resections under fluorescein guidance.

Non-CE resection No significant between-group differences were found in preoperative CE/NCE volumes or postoperative NCE residual volumes, consistent with fluorescein primarily highlighting BBB-disrupted (enhancing) tissue.

MGMT association MGMT promoter methylation was associated with higher likelihood of achieving nonresidual CE (complete CE resection), P = .005; fluorescein guidance and MGMT status were significant predictors of nonresidual CE.

Survival Overall survival did not significantly differ between fluorescein-guided and WL groups (log-rank P = .15), while MGMT-methylated patients had significantly better survival than unmethylated (P = .019; HR = 0.52).

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Exploring the Diagnostic Test Accuracy of MicroRNAs as Potential Biomarkers for Glioblastoma

Neurosurgery 98:1221–1230, 2026

This systematic review and meta-analysis evaluates microRNA (miRNA)–based liquid biopsies for diagnosing glioblastoma (GBM), synthesizing data from 15 studies and 28 biomarker evaluations across 868 samples. Key diagnostic metrics—pooled sensitivity 0.84 and specificity 0.89—indicate strong potential, with miR-21 showing the highest accuracy among single-miRNA assays.

The report details search strategy, inclusion criteria, statistical methods, subgroup analyses (miRNA type, biofluid source, control type), and study quality assessment. Limitations include methodological heterogeneity, high risk of bias in patient selection, inconsistent reporting (CSF source, IDH status), and small cohort sizes, underscoring need for standardized clinical validation.

Aim Evaluate the diagnostic accuracy of microRNA (miRNA) liquid biopsies (blood/serum/plasma/CSF) for diagnosing glioblastoma (GBM) via systematic review and meta-analysis.

Methods PRISMA-guided searches of Ovid Medline and Embase (updated through Oct 16, 2024); included studies had histologic GBM confirmation and extractable 2×2 diagnostic data; pooled estimates generated using a random-effects bivariate model.

Evidence base 15 included articles (published 2011–2022) provided 28 miRNA evaluations, totaling 868 samples from 551 GBM patients and 811 samples from 578 controls.

Overall accuracy Pooled sensitivity 0.84 and specificity 0.89, with heterogeneity of 66% (sensitivity) and 39% (specificity); pooled AUC 0.89.

Likelihood ratios Pooled PLR 7.26, NLR 0.19, and DOR 40.17, indicating strong overall discriminatory performance.

Key biomarker miR-21 showed the highest pooled performance among assessed groupings (sensitivity 0.90, specificity 0.95).

Subgroups Single miRNAs had higher specificity than multi-miRNA panels, while diagnostic capability did not differ clearly by biofluid source (CSF vs blood) in this dataset.

Limitations All included studies had high risk of bias in patient selection, and many had bias in index test interpretation/flow-timing; limited CSF comparisons and inconsistent qPCR thresholds/normalization contributed to heterogeneity and constrain clinical translation without standardization and validation.

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Global economic differences in modern glioblastoma care – a systematic review

Acta Neurochirurgica (2026) 168:89

This systematic review quantifies global cost and cost-effectiveness differences in contemporary glioblastoma (GBM) care, analyzing 21 studies standardized to 2024 USD. It reports extreme heterogeneity in direct medical costs—from about $18,908 in India to $356,481 in the United States—and identifies inpatient care and adjuvant therapies as primary cost drivers in high-income settings.

Economic models reveal that the full Stupp protocol often exceeds willingness-to-pay thresholds in middle- and low-income countries, while surgical resection and 5‑ALA fluorescence-guided surgery show relatively favorable cost-effectiveness. The authors call for standardized cost reporting and inclusion of societal perspectives to improve cross-country comparisons and policy decisions.

Purpose Quantified global differences in costs and cost-effectiveness of modern Stupp-protocol–based glioblastoma care via a systematic review.

Methods Searched PubMed/MEDLINE/Cochrane to Dec 1, 2025 using (Glioblastoma OR GBM) AND (costs OR cost-effectiveness OR economic burden); included studies with quantifiable economic outcomes from 2005 onward, yielding 21 eligible studies.

Standardization Converted all reported costs to 2024 USD by inflating with country-specific CPI to 2024 and converting using 2024 PPP rates.

Direct costs range Direct medical costs were highly heterogeneous, from about $356,481 (United States) to about $18,908 (India), across 15,547 real-world patients.

Cost drivers (Western systems) Adjuvant treatment and inpatient care were major contributors to direct medical costs in western countries (with inpatient care and radiotherapy prominent in US analyses).

Stupp protocol affordability The Stupp protocol exceeded willingness-to-pay thresholds in middle-income/resource-limited settings, indicating substantial financial burden in those contexts.

TTF cost-effectiveness variability Tumor treating fields (TTF) showed very high ICERs in France (≈ $862k–$940k per LYG) and $252,590 per LYG in the US, but a more favorable estimate of $45,813.91 per QALY in China.

Key implication Uniform, standardized cost reporting is needed to better compare cost-effectiveness across countries; economic findings also underscore the role of surgery as a cost-effective component of modern GBM management.

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Determinants of survival after re-resection for recurrent glioblastoma: a meta-analysis

Acta Neurochirurgica (2026) 168:11

This systematic review and meta-analysis examines prognostic factors affecting survival after re-resection for recurrent glioblastoma, synthesizing data from 30 studies (1,741 pooled patients). Key findings identify gross total resection and MGMT promoter methylation as strong positive predictors, while age and low preoperative KPS associate with poorer outcomes; adjuvant therapies and time to re-resection showed inconsistent effects.

The paper details search methods, risk-of-bias assessment, statistical approaches, sensitivity analyses for IDH status, and study heterogeneity limitations. Conclusions emphasize patient selection for re-resection based on functional status and molecular markers and call for prospective, standardized trials and individual-patient data analyses to refine management of recurrent glioblastoma.

Gross Total Resection (GTR): Achieving GTR at re-resection for recurrent glioblastoma is significantly associated with improved survival compared to subtotal resection (pooled HR ~0.52–0.70, p < 0.001).

MGMT Promoter Methylation: Patients with methylated MGMT promoter status at recurrence have significantly better survival following re-resection (multivariate HR = 0.45, 95% CI: 0.27–0.76, p < 0.01).

Preoperative Karnofsky Performance Status (KPS): A KPS score <70 before re-resection is strongly associated with poorer survival outcomes (HR = 2.25, 95% CI: 1.59–3.19, p < 0.001).

Age: Older age is modestly associated with worse survival after re-resection, but the effect size is small (HR = 1.02, 95% CI: 1.01–1.03, p < 0.001); age alone should not preclude aggressive treatment.

Adjuvant Chemotherapy and Radiotherapy: No significant survival benefit was found for adjuvant chemotherapy (HR = 0.69, p = 0.33), radiotherapy (HR = 0.62, p = 0.50), or combined chemoradiotherapy after re-resection.

Time to Re-resection: Longer time intervals between initial surgery and re-resection did not show a statistically significant association with improved survival (HR = 0.69, p = 0.16).

Personalized Approach: Selection for re-resection should prioritize patients with good performance status, favorable tumor characteristics, and methylated MGMT promoter, with GTR as a key goal.

Evidence Limitations: Most included studies were retrospective with heterogeneity in definitions and reporting; high-quality prospective trials are needed to refine prognostic assessments and treatment strategies.

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Indirect cognitive mapping in glioma surgery in patients not eligible for awake craniotomy

Acta Neurochirurgica (2025) 167:289

This article presents a neurosurgical technique for indirectly mapping cognitive subcortical white matter pathways during glioma resection in patients who cannot undergo awake craniotomy. Using preoperative DTI and fMRI to create a 3D functional map, the team employs intraoperative monopolar subcortical motor stimulation as a live landmark to infer and protect nearby cognitive tracts like the arcuate fasciculus and IFOF.

Three illustrative cases demonstrate planning limits based on measured motor stimulation thresholds (approx. 1 mA ≈ 1 mm) and show safe resections with preserved cognitive and motor function. The report discusses indications, limitations versus awake mapping, importance of patient counselling about transient deficits, and integration of neuronavigation, tractography, and intraoperative motor mapping.

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Factors associated with poor prognosis in elderly biopsy‑only glioblastoma patients

Acta Neurochirurgica (2025) 167:273

In elderly glioblastoma patients undergoing biopsy only, poor preoperative performance status, central tumor location, and larger tumor volume were associated with reduced three-month survival and lower treatment completion rates, highlighting the need for careful preoperative assessment and personalized counseling in this vulnerable group.

Study investigated elderly patients (>65 years) with glioblastoma (GBM) who underwent biopsy only, not surgical resection.

• Median overall survival (OS) was 4.6 months; only half completed oncological treatment.

• Poor preoperative performance status (PS), central tumor location, and larger tumor volume were independently associated with reduced three-month survival.

• Poor PS was the only independent predictor for not completing oncological treatment; these patients had very poor survival (median OS 1.6 months).

• Completion of treatment was linked to longer survival (median OS 8.3 months for completers vs. 3.5 months for non-completers).

• Findings suggest limited benefit of biopsy and oncological treatment in elderly GBM patients with poor PS.

• Results can help guide preoperative counseling and decision-making for this vulnerable patient group.

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Dynamic Tumor in Situ Fluid Circulating Tumor DNA Postsurgery Effectively Predicts Recurrence and Clinical Benefits for Glioblastomas

Neurosurgery 97:671–680, 2025

Dynamic monitoring of tumor in situ fluid circulating tumor DNA (TISF-ctDNA) after glioblastoma surgery predicts recurrence earlier than imaging, effectively identifies molecular residual disease, and serves as a robust prognostic biomarker. TISF-ctDNA status guides treatment response assessment and may enable more personalized, timely interventions for GBM patients.

• TISF-ctDNA (tumor in situ fluid circulating tumor DNA) is a promising biomarker for monitoring molecular residual disease (MRD) and recurrence in glioblastoma (GBM) patients after surgery.

• In a prospective study of 37 GBM patients, TISF-ctDNA positivity after surgery was detected in 62.2% of cases and predicted a higher risk of recurrence and shorter progression-free survival (PFS).

• TISF-ctDNA positivity preceded imaging-detected recurrence by a median of 71 days, allowing for earlier intervention.

• Conversion from TISF-ctDNA positive to negative during adjuvant therapy was associated with improved overall survival.

• TISF-ctDNA showed high sensitivity (86.2%) and specificity (100%) in detecting postsurgical MRD recurrence.

• Common tumor gene mutations (EGFR, TP53, PTEN, NF1) did not significantly impact prognosis in this cohort.

• TISF-ctDNA monitoring is less effective for detecting distant tumor recurrences.

• The study supports TISF-ctDNA as an early, noninvasive tool for personalized GBM management, though larger studies are needed for validation.

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Ventricular Entry During Glioblastoma Resection is Associated With Reduced Survival and Increased Risk of Distant Recurrence

Neurosurgery 97:601–611, 2025

Ventricular entry (VE) during glioblastoma resection is an independent risk factor for reduced overall survival and increased distant recurrence, including leptomeningeal dissemination. VE may diminish the survival benefit of gross-total resection, especially in tumors contacting the subventricular zone. Surgical strategies should weigh VE risks against maximal tumor removal.

• Ventricular entry (VE) during glioblastoma (GBM) resection is associated with significantly reduced overall survival (OS) and increased risk of distant recurrence and leptomeningeal dissemination (LMD), independent of other prognostic factors.

• Patients with VE had a median OS of 12 months versus 18 months for non-VE, and higher rates of distant recurrence (63.9% vs 39.7%).

• VE is more common in tumors contacting the subventricular zone (SVZ), and even among these, VE further reduces survival (12 vs 17 months).

• Gross-total resection (GTR) without VE provides the longest survival; GTR with VE does not significantly improve survival over less extensive resections with VE.

• VE is also associated with higher rates of postoperative hydrocephalus and need for external ventricular drains.

• Mechanistically, VE may facilitate tumor cell seeding into cerebrospinal fluid, promoting multifocal recurrences and LMD.

• Neurosurgeons should carefully weigh the risks of VE against the benefits of maximal tumor resection in surgical planning.

• Further prospective, multicenter studies are needed to clarify the risks and guide surgical strategies for GBM involving the SVZ.

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Is FLAIRectomy Directly Correlated with Prolonged Survival in Glioblastoma? A Prospective National Multicenter Study on Correlation Between Extent of Tumor Resection and Clinical Outcome

Neurosurgery 97:489–500, 2025

This multicenter prospective study shows that the extent of FLAIRectomy (resection of FLAIR-positive areas) in glioblastoma is a stronger predictor of survival than traditional resection, with higher EOFR significantly improving progression-free and overall survival, especially in IDH-mutant tumors, without increasing neurological complications.

• FLAIRectomy, or resection of FLAIR-MRI hyperintense regions beyond the contrast-enhancing tumor, was studied in a prospective multicenter cohort of 150 glioblastoma patients.

• A higher extent of FLAIR resection (EOFR) was associated with significantly improved overall survival (OS) and progression-free survival (PFS), more so than resection of contrast-enhancing tumor alone.

• Each 1% increase in EOFR correlated with a 6.8% reduction in mortality risk for IDH-wildtype and 12.1% for IDH-mutant tumors.

• Mean OS was 28.4 months and mean PFS was 16.3 months in the study cohort.

• IDH1 mutation status was also associated with longer survival, but EOFR remained an independent predictor after adjustment.

• AI analysis confirmed that patients with higher EOFR clustered with longer survival.

• Neurological safety was addressed with intraoperative neuromonitoring and careful planning; permanent deficits occurred in 9/150 patients.

• The study concludes that FLAIR-based supramarginal resection may be a more reliable predictor of survival in glioblastoma than conventional imaging-guided resection.

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Safety and therapeutic impact of stereotactic biopsy in very elderly patients with brain tumors

J Neurosurg 143:194–203, 2025

Stereotactic brain biopsy in patients aged ≥80 is safe, with high diagnostic yield (96.2%) and low persistent neurological deficit (1.9%). Prebiopsy Karnofsky Performance Status ≥70% predicts full adjuvant therapy and longer survival. Biopsy findings frequently alter management, supporting its use in very elderly brain tumor patients.

• Stereotactic brain biopsy in patients aged ≥80 years is safe and has a high diagnostic yield (96.2%).

• Symptomatic complication rate was 6.2%, with persistent neurological deficit in 1.9% and a procedure-related mortality of 0.5%.

• The biopsy changed the suspected diagnosis in 11.1% of cases, influencing patient management.

• 80.7% of patients received adjuvant treatment after biopsy; 19.3% received palliative care.

• A Karnofsky Performance Status (KPS) score ≥70% was the only significant predictor for receiving full adjuvant therapy and longer overall survival (OS).

• Median OS after biopsy was 5.6 months; longer in patients with PCNSL or methylated MGMT promoter in glioma.

• No significant increase in complications was seen with deep-seated tumors, anticoagulant use, or advanced age (≥85 or ≥90 years).

• The study supports considering biopsy for very elderly patients when technically feasible and patient condition is good.

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Prognostic value of manual versus automatic methods for assessing extents of resection and residual tumor volume in glioblastoma

J Neurosurg 142:1298–1306, 2025

This study compares manual and automatic methods for assessing tumor resection extent and residual volume in glioblastoma patients. It finds that both methods have comparable prognostic value, suggesting that automatic segmentation with Raidionics is a viable alternative for future studies.

• Objective: The study compares the prognostic value of manual versus automatic methods for assessing the extent of resection (EOR) and residual tumor (RT) volume in glioblastoma patients.

• Methods: Patients from 12 hospitals in Europe and North America underwent glioblastoma resection and were included in the study. Data were collected from local tumor registries and patient medical records.

• Results: Both manual and automatic RT volumes were negative prognostic factors for overall survival. Automatic segmentation with Raidionics showed comparable prognostic properties to manual measurements.

• Automatic Segmentation: Raidionics, an open-access software, performed automatic segmentation using pretrained deep learning models, which showed high quality and robustness.

• Survival Analysis: Cox regression models indicated that patients with gross-total resection had significantly longer overall survival compared to those with subtotal resection.

• Advantages of Automatic Methods: Automatic segmentation offers fast, quantitative image assessments and reduces interobserver variability, making it suitable for clinical trials.

• Limitations: Some cases showed a mismatch between manual and automatic segmentation, often due to poor-quality MR images or heterogeneous tumors.

• Conclusion: Automatic segmentation is a viable alternative to manual methods for evaluating tumor remnants, with similar prognostic value for survival in glioblastoma patients.

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Clinical Predictors of Overall Survival in Very Elderly Patients With Glioblastoma: A National Cancer Database Multivariable Analysis

Neurosurgery 96:373–385, 2025

• Study Focus: The study analyzes clinical predictors of overall survival in very elderly patients (aged 80 and older) with glioblastoma, using data from the National Cancer Database.

• Patient Demographics: It includes 578 very elderly patients and 2836 elderly patients (aged 65-79), highlighting differences in insurance status and treatment patterns.

• Treatment Patterns: Very elderly patients are less likely to receive gross total resection (GTR), radiotherapy (RT), or chemotherapy (CT) compared to younger elderly counterparts, despite these treatments improving overall survival.

• Survival Outcomes: GTR, RT, and CT are associated with improved survival in very elderly patients, suggesting aggressive treatment may benefit selected patients.

• Statistical Methods: The study employs multivariable regression analysis and Cox proportional-hazards models to assess the effects of age and treatment on survival.

• Key Findings: Aggressive treatment approaches, including GTR, RT, and CT, should be considered for very elderly patients, aligning with patient and family goals.

• Limitations: The study acknowledges limitations in meeting the Cox proportional hazard assumption and suggests further research on quality of life post-treatment.

• Conclusion: The study supports offering standard multimodal treatment protocols for glioblastoma to patients aged 65 and older, enhancing external validity across the U.S.

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Long-term survivors in 976 supratentorial glioblastoma, IDH-wildtype patients

J Neurosurg 142:174–186, 2025

Glioblastoma, isocitrate dehydrogenase (IDH)–wildtype is the most aggressive glioma with poor outcomes. The authors explored survival rates and factors associated with long-term survival in patients harboring a glioblastoma, IDH-wildtype.

METHODS In an observational, retrospective, single-center study, the authors examined the medical records of 976 adults newly diagnosed with supratentorial glioblastomas, IDH-wildtype between January 2000 and January 2021. They analyzed clinical-, imaging-, and treatment-related factors associated with 2-year and 5-year survival.

RESULTS The median overall survival was 11.2 months (12.2 months for patients included after 2005 and the introduction of standard combined chemoradiotherapy). The median progression-free survival was 9.4 months (10.0 months for patients included after 2005). Overall, 17.6% of patients reached a 2-year overall survival, while 2.2% of patients reached a 5-year overall survival. Furthermore, 6.6% of patients survived 2 years without progression, while 1.1% of patients survived 5 years without progression. Two factors that were consistently associated with 2-year and 5-year survival were first-line oncological treatment with standard combined chemoradiotherapy and methylated O 6 -methylguanineDNA methyltransferase promoter. Other factors that were significantly associated with 2-year or 5-year survival were age at diagnosis ≤ 60 years, headaches or signs of raised intracranial pressure at diagnosis, cortical contact of contrast enhancement, no contrast enhancement crossing the midline on initial imaging, total or subtotal tumor resection, and a second line of oncological treatment at recurrence. Within 21 cases of 5-year survival, 18 were confirmed to be glioblastomas, IDH-wildtype, and 7 of the 5-year survivors (38.9%) had additional genetic alterations: 3 cases had an FGFR mutation or fusion, 3 cases had a PIK3CA mutation, 1 case had a PTPN11 mutation, and 1 case had a PMS2 mutation in the context of constitutional mismatch repair deficiency syndrome.

CONCLUSIONS Five-year overall survival in patients with glioblastoma, IDH-wildtype is extremely low. Predictors of a longer survival are mostly treatment factors, emphasizing the importance of a complete oncological treatment plan, when achievable. Glioblastoma, IDH-wildtype 5-year survivors could be screened for actionable targets in case of recurrence.

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Berberine as a potential enhancer for 5-ALA–mediated fluorescence in glioblastoma

J Neurosurg 141:653–663, 2024

The prognosis of glioblastoma (GBM) correlates with residual tumor volume after surgery. In fluorescenceguided surgery, 5-aminolevulinic acid (ALA) has been used to maximize resection while avoiding neurological morbidity. However, not all tumor cells, particularly glioma stem cells (GSCs), display 5-ALA–mediated protoporphyrin IX (PpIX) fluorescence (5-ALA fluorescence). The authors searched for repositioned drugs that affect mitochondrial functions and energy metabolism, identifying berberine (BBR) as a potential enhancer of 5-ALA fluorescence. In this study, they investigated whether BBR can enhance 5-ALA fluorescence in GSCs and whether BBR can be applied to clinical practice as a 5-ALA fluorescence enhancer.

METHODS The effects of BBR on 5-ALA fluorescence in glioma and GSCs were evaluated by flow cytometry (fluorescence-activated cell sorting [FACS]) analysis. As 5-ALA is metabolized for heme synthesis, the effects of BBR on mRNA expressions of 7 enzymes in the heme-synthesis pathway were analyzed. Enzymes showing significantly higher expression than control in all cells were identified and protein analysis was performed. To examine clinical availability, the detectability and cytotoxicity of BBR in tumor-transplanted mice were analyzed.

RESULTS Fluorescence microscopy revealed much more intense 5-ALA fluorescence in both GSCs and non-stem cells with 5-ALA and BBR than with 5-ALA alone. FACS showed that BBR greatly enhanced 5-ALA fluorescence compared with 5-ALA alone, and enhancement was much higher for GSCs than for glioma cells. Among the 7 enzymes examined, BBR upregulated mRNA expressions of ALA synthetase 1 (ALAS1) more highly in all cells, and activated ALAS1 through deregulating ALAS1 activity inhibited by the negative feedback of heme. An in vivo study showed that 5-ALA fluorescence with 5-ALA and BBR was significantly stronger than with 5-ALA alone, and the sensitivity and specificity of BBR-enhanced fluorescence were both 100%. In addition, BBR did not show any cytotoxicity for normal brain tissue surrounding the tumor mass.

CONCLUSIONS BBR enhanced 5-ALA–mediated PpIX fluorescence by upregulating and activating ALAS1 through deregulation of negative feedback inhibition by heme. BBR is a clinically used drug with no side effects. BBR is expected to significantly augment fluorescence-guided surgery and photodynamic therapy.

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Efficacy and Safety of Carmustine Wafer Implantation After Ventricular Opening in Glioblastomas, Isocitrate Dehydrogenase-Wildtype, in Adults

Neurosurgery 94:1227–1236, 2024

We assessed the impact of ventricular opening on postoperative complications and survival of carmustine wafer implantation during surgery of newly diagnosed supratentorial glioblastomas, isocitrate dehydrogenase (IDH)-wildtype in adults.

METHODS: We performed an observational, retrospective, single-center cohort study at a tertiary surgical neurooncological center between January 2006 and December 2021.

RESULTS: One hundred ninety-four patients who benefited from a first-line surgical resection with carmustine wafer implantation were included. Seventy patients (36.1%) had a ventricular opening. We showed that ventricular opening (1) did not increase overall postoperative complication rates (P = .201); (2) did not worsen the early postoperative Karnofsky Performance Status score (P = .068); (3) did not increase the time interval from surgery to adjuvant oncological treatment (P = .458); (4) did not affect the completion of the standard radiochemotherapy protocol (P = .164); (5) did not affect progression-free survival (P = .059); and (6) did not affect overall survival (P = .142).

CONCLUSION: In this study, ventricular opening during first-line surgical resection did not affect the survival and postoperative complications after use of carmustine wafer implantation in adult patients with a newly diagnosed supratentorial glioblastoma, IDH-wildtype. This warrants a prospective and multicentric study to clearly assess the impact of the ventricular opening after carmustine wafer implantation in glioblastoma, IDH-wildtype.

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Use of 5-ALA fluorescence–guided surgery versus white-light conventional microsurgery for the resection of newly diagnosed glioblastomas (RESECT study): a French multicenter randomized phase III study

J Neurosurg 140:987–1000, 2024

Only one phase III prospective randomized study, published in 2006, has assessed the performance of 5-aminolevulinic acid (5-ALA) fluorescence–guided surgery (FGS) for glioblastoma resection. The aim of the RESECT study was to compare the onco-functional results associated with 5-ALA fluorescence and with white-light conventional microsurgery in patients with glioblastoma managed according to the current standards of care.

METHODS This was a phase III prospective randomized single-blinded study, involving 21 French neurosurgical centers, comparing 5-ALA FGS with white-light conventional microsurgery in patients with glioblastoma managed according to the current standards of care, including neuronavigation use and postoperative radiochemotherapy. Randomization was performed in a 1:1 ratio stratified by institution. 5-ALA (20 mg/kg) or placebo (ascorbic acid) was administered orally 3–5 hours before the incision. The primary endpoint was the rate of gross-total resection (GTR) blindly assessed by an independent committee. Patients without a confirmed pathological diagnosis of glioblastoma or with unavailable postoperative MRI studies were excluded from the per-protocol analysis.

RESULTS Between March 2013 and August 2016, a total of 171 patients were assigned to the 5-ALA fluorescence group (n = 88) or to the placebo group (n = 83). Twenty-four cases were excluded because the WHO histological criteria of grade 4 glioma were not met. The proportion of GTR was significantly higher in the 5-ALA fluorescence group (53/67, 79.1%) than in the placebo group (33/69, 47.8%; p = 0.0002). After adjustment for age, preoperative Karnofsky Performance Scale score, and tumor location, GTR was still associated with 5-ALA fluorescence (OR 4.13 [95% CI 1.94–8.79]). The mean 7-day postoperative Karnofsky Performance Scale score (≥ 80% in 49/71, 69.0% [5-ALA group]; 50/71, 70.4% [placebo group], p = 0.86) and the proportion of patients with a worsened neurological status 3 months postoperatively (9/68, 13.2% [5-ALA group]; 9/70, 12.9% [placebo group], p = 0.95) were similar between groups. Adverse events related to 5-ALA intake were rare and consisted of photosensitization in 4/87 (4.6%) patients and hepatic cytolysis in 1/87 (1.1%) patients. The 6-month PFS (70.2% [95% CI 57.7%–79.6%] and 68.4% [95% CI 55.7%–78.1%]; p =0.39) and 24-month OS (30.1% [95% CI 18.9%–42.0%] and 37.7% [95% CI 25.8%–49.5%]; p = 0.89) did not significantly differ. In multivariate analysis, GTR was an independent predictor of PFS (hazard ratio 0.56 [95% CI 0.36–0.86], p =0.008) and OS (hazard ratio 0.65 [95% CI 0.42–1.01], p = 0.05). The use of 5-ALA FGS generates a significant extra cost of 2732.36€ (95% CI 1658.40€–3794.11€).

CONCLUSIONS The authors found that 5-ALA FGS is an easy-to-use, cost-effective, and minimally time-consuming technique that safely optimizes the extent of resection in patients harboring glioblastoma amenable to a large resection.

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Beyond fluorescence‑guided resection: 5‑ALA‑based glioblastoma therapies

Acta Neurochirurgica (2024) 166:163

Glioblastoma is the most common primary malignant brain tumor. Despite advances in multimodal concepts over the last decades, prognosis remains poor. Treatment of patients with glioblastoma remains a considerable challenge due to the infiltrative nature of the tumor, rapid growth rates, and tumor heterogeneity.

Standard therapy consists of maximally safe microsurgical resection followed by adjuvant radio- and chemotherapy with temozolomide. In recent years, local therapies have been extensively investigated in experimental as well as translational levels.

External stimuli-responsive therapies such as Photodynamic Therapy (PDT), Sonodynamic Therapy (SDT) and Radiodynamic Therapy (RDT) can induce cell death mechanisms via generation of reactive oxygen species (ROS) after administration of five-aminolevulinic acid (5-ALA), which induces the formation of sensitizing porphyrins within tumor tissue.

Preliminary data from clinical trials are available. The aim of this review is to summarize the status of such therapeutic approaches as an adjunct to current standard therapy in glioblastoma.

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Sodium fluorescein uptake by the tumor microenvironment in human gliomas and brain metastases

J Neurosurg 140:958–967, 2024

Intravenous sodium fluorescein (SF) is increasingly used during surgery of gliomas and brain metastases to improve tumor resection. Currently, SF is believed to permeate the brain regions where the blood-brain barrier (BBB) is damaged and to accumulate in the extracellular space but not in tumor or healthy cells, making it possible to demarcate tumor margins to guide resection. By evaluating the immune contexture of a number of freshly resected gliomas and brain metastases from patients undergoing SF-guided surgery, the authors recurrently observed fluorescence-positive cells. Therefore, the aim of this study was to determine if SF accumulates inside the cells of the tumor microenvironment (TME), and if so, in which type of cells, and whether incorporation can also be observed in the leukocytes of peripheral blood.

METHODS Freshly resected tumor specimens were dissociated to single cells and analyzed by multiparametric flow cytometry. Peripheral blood leukocytes, macrophages, and a glioma cell line were treated with SF in vitro, and their cell uptake was assessed by multiparametric and imaging flow cytometry and by confocal microscopy.

RESULTS The ex vivo and in vitro analyses revealed that SF accumulates intracellularly in leukocytes as well as in tumor cells, but with a high variability of incorporation in the different cell subsets analyzed. Myeloid cells showed the highest level of fluorescence. In vitro uptake experiments showed that SF accumulation increases over time. The imaging analyses confirmed the internalization of the compound inside the cells.

CONCLUSIONS SF is not just a marker of BBB damage, but its intracellular detection suggests that it selectively accumulates intracellularly. Future efforts should target the mechanisms of its differential uptake by the different TME cell types in depth.

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Minimally invasive keyhole approach for supramaximal frontal glioma resections

J Neurosurg 140:949–957, 2024

The authors aimed to review the frontal lobe’s surgical anatomy, describe their keyhole frontal lobectomy technique, and analyze the surgical results.

METHODS Patients with newly diagnosed frontal gliomas treated using a keyhole approach with supramaximal resection (SMR) from 2016 to 2022 were retrospectively reviewed. Surgeries were performed on patients asleep and awake. A human donor head was dissected to demonstrate the surgical anatomy. Kaplan-Meier curves were used for survival analysis.

RESULTS Of the 790 craniotomies performed during the study period, those in 47 patients met our inclusion criteria. The minimally invasive approach involved four steps: 1) debulking the frontal pole; 2) subpial dissection identifying the sphenoid ridge, olfactory nerve, and optic nerve; 3) medial dissection to expose the falx cerebri and interhemispheric structures; and 4) posterior dissection guided by motor mapping, avoiding crossing the inferior plane defined by the corpus callosum. A fifth step could be added for nondominant lesions by resecting the inferior frontal gyrus. Perioperative complications were recorded in 5 cases (10.6%). The average hospital length of stay was 3.3 days. High-grade gliomas had a median progression-free survival of 14.8 months and overall survival of 23.9 months.

CONCLUSIONS Keyhole approaches enabled successful SMR of frontal gliomas without added risks. Robust anatomical knowledge and meticulous surgical technique are paramount for obtaining successful resections.

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Awake Versus Asleep Craniotomy for Patients With Eloquent Glioma: A Systematic Review and Meta-Analysis

Neurosurgery 94:38–52, 2024

Awake vs asleep craniotomy for patients with eloquent glioma is debatable. This systematic review and meta-analysis sought to compare awake vs asleep craniotomy for the resection of gliomas in the eloquent regions. METHODS: MEDLINE and PubMed were searched from inception to December 13, 2022. Primary outcomes were the extent of resection (EOR), overall survival (month), progression-free survival (month), and rates of neurological deficit, Karnofsky performance score, and seizure freedom at the 3-month follow-up. Secondary outcomes were duration of operation (minute) and length of hospital stay (LOS) (day).

RESULTS: Fifteen studies yielded 2032 patients, from which 800 (39.4%) and 1232 (60.6%) underwent awake and asleep craniotomy, respectively. The meta-analysis concluded that the awake group had greater EOR (mean difference [MD]= MD= 8.52 [4.28, 12.76], P < .00001), overall survival (MD = 2.86 months [1.35, 4.37], P = .0002), progression-free survival (MD = 5.69 months [0.75, 10.64], P = .02), 3-month postoperative Karnofsky performance score (MD = 13.59 [11.08, 16.09], P < .00001), and 3-month postoperative seizure freedom (odds ratio = 8.72 [3.39, 22.39], P < .00001). Furthermore, the awake group had lower 3-month postoperative neurological deficit (odds ratio = 0.47 [0.28, 0.78], P = .004) and shorter LOS (MD = -2.99 days [-5.09, -0.88], P = .005). In addition, the duration of operation was similar between the groups (MD = 37.88 minutes [-34.09, 109.86], P = .30).

CONCLUSION: Awake craniotomy for gliomas in the eloquent regions benefits EOR, survival, postoperative neurofunctional outcomes, and LOS. When feasible, the authors recommend awake craniotomy for surgical resection of gliomas in the eloquent regions.

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